Effects of Intranasal Naloxone on Hypoglycemia-Associated Autonomic Failure (HAAF) in Susceptible Individuals.

CONTEXT: Hypoglycemia-associated autonomic failure (HAAF), defined as blunting of counter-regulatory hormone and symptom responses to recurrent hypoglycemia, remains a therapeutic challenge in diabetes treatment. The opioid system may play a role in HAAF pathogenesis since activation of opioid receptors induces HAAF. Blockade of opioid receptors with intravenous naloxone ameliorates HAAF experimentally, yet is not feasible therapeutically. OBJECTIVE: To investigate the effects of opioid receptor blockade with intranasal naloxone on experimentally-induced HAAF. DESIGN: Randomized, double-blinded, placebo-controlled crossover study. SETTING: Academic research center. PARTICIPANTS: Healthy non-diabetic volunteers. INTERVENTIONS: Paired two-day studies, 5-10 weeks apart, each consisting of three consecutive hypoglycemic episodes (hyperinsulinemic hypoglycemic clamps, glucose nadir: 54 mg/dL): two on day 1 with administration of intranasal naloxone vs. placebo, followed by the third episode on day 2. MAIN OUTCOME MEASURES: Differences in counter-regulatory hormones responses and hypoglycemia symptoms between first and third hypoglycemic episodes in naloxone vs. placebo studies. RESULTS: Out of 17 participants, 9 developed HAAF, confirming variable inter-individual susceptibility. Among participants susceptible to HAAF, naloxone maintained some hormonal and symptomatic responses to hypoglycemia and prevented the associated requirement for increased glucose infusion. Unexpectedly, naloxone reduced plasma epinephrine and growth hormone responses to the first hypoglycemic episode but prevented further reduction with subsequent hypoglycemia. CONCLUSIONS: This is the first study to report that intranasal naloxone, a widely used opioid receptor antagonist, may ameliorate some features of HAAF. Further investigation is warranted into mechanisms of variable inter-individual susceptibility to HAAF and the effects of intranasal naloxone in people with diabetes at risk for HAAF.

Plasma Epinephrine Contributes to the Development of Experimental Hypoglycemia-Associated Autonomic Failure.

BACKGROUND: Recurrent hypoglycemia blunts counter-regulatory responses to subsequent hypoglycemic episodes, a syndrome known as hypoglycemia-associated autonomic failure (HAAF). Since adrenergic receptor blockade has been reported to prevent HAAF, we investigated whether the hypoglycemia-associated rise in plasma epinephrine contributes to pathophysiology and reported interindividual differences in susceptibility to HAAF. METHODS: To assess the role of hypoglycemia-associated epinephrine responses in the susceptibility to HAAF, 24 adult nondiabetic subjects underwent two 2-hour hyperinsulinemic hypoglycemic clamp studies (nadir 54 mg/dL; 0-2 hours and 4-6 hours) on Day 1, followed by a third identical clamp on Day 2. We challenged an additional 7 subjects with two 2-hour infusions of epinephrine (0.03 µg/kg/min; 0-2 hours and 4-6 hours) vs saline on Day 1 followed by a 200-minute stepped hypoglycemic clamp (90, 80, 70, and 60 mg/dL) on Day 2. RESULTS: Thirteen out of 24 subjects developed HAAF, defined by ≥20% reduction in average epinephrine levels during the final 30 minutes of the third compared with the first hypoglycemic episode (P < 0.001). Average epinephrine levels during the final 30 minutes of the first hypoglycemic episode were 2.3 times higher in subjects who developed HAAF compared with those who did not (P = 0.006).Compared to saline, epinephrine infusion on Day 1 reduced the epinephrine responses by 27% at the 70 and 60 mg/dL glucose steps combined (P = 0.04), with a parallel reduction in hypoglycemic symptoms (P = 0.03) on Day 2. CONCLUSIONS: Increases in plasma epinephrine reproduce key features of HAAF in nondiabetic subjects. Marked interindividual variability in epinephrine responses to hypoglycemia may explain an individual's susceptibility to developing HAAF.

Acute milk-alkali syndrome

Summary: A 74-year-old woman presented with progressive lethargy, confusion, poor appetite and abdominal pain. She was found to have non-PTH-mediated severe hypercalcemia with renal failure and metabolic alkalosis. Extensive workup for hypercalcemia to rule out alternate etiology was unrevealing. Upon further questioning, she was taking excess calcium carbonate (Tums) for her worsening heartburn. She was diagnosed with milk-alkali syndrome (MAS). Her hypercalcemia and alkalosis recovered completely with aggressive hydration along with improvement in her renal function. High index of suspicion should be maintained and history of drug and supplements, especially calcium ingestion, should be routinely asked in patients presenting with hypercalcemia to timely diagnose MAS and prevent unnecessary tests and treatments. Learning Points: Suspect milk-alkali syndrome in patients with hypercalcemia, metabolic alkalosis and renal failure, especially in context of ingestion of excess calcium-containing supplements. Careful history of over-the-counter medications, supplements and diet is crucial to diagnose milk-alkali syndrome. Milk-alkali syndrome may cause severe hypercalcemia in up to 25­30% of cases.

Primary Hyperparathyroidism in Pregnancy: Successful Parathyroidectomy during First Trimester.

Primary hyperparathyroidism in pregnancy can result in significant maternal and fetal complications. When indicated, prompt parathyroidectomy in the early second trimester is considered the treatment of choice. Pregnant patients with primary hyperparathyroidism who have an indication for parathyroidectomy during the first trimester represent a therapeutic challenge. We present the case of a 32-year-old primigravida who presented with symptomatic hypercalcemia from her primary hyperparathyroidism. She remained symptomatic despite aggressive conservative management and underwent parathyroidectomy in her first trimester with excellent outcomes.

Potential approaches to prevent hypoglycemia-associated autonomic failure.

Clear health benefits are associated with intensive glucose control in type 1 diabetes mellitus (T1DM). However, maintaining near-normal glycemia remains an elusive goal for many patients, in large part owing to the risk of severe hypoglycemia. In fact, recurrent episodes of hypoglycemia lead to 'hypoglycemia-associated autonomic failure' (HAAF), characterized by defective counter-regulatory responses to hypoglycemia. Extensive studies to understand the mechanisms underlying HAAF have revealed multiple potential etiologies, suggesting various approaches to prevent the development of HAAF. In this review, we present an overview of the literature focused on pharmacological approaches that may prevent the development of HAAF. The purported underlying mechanisms of HAAF include: 1) central mechanisms (opioid receptors, ATP-sensitive K+(KATP) channels, adrenergic receptors, serotonin selective receptor inhibitors, γ-aminobuyric acid receptors, N-methyl D-aspartate receptors); 2) hormones (cortisol, estrogen, dehydroepiandrosterone (DHEA) or DHEA sulfate, glucagon-like peptide-1) and 3) nutrients (fructose, free fatty acids, ketones), all of which have been studied vis-à-vis their ability to impact the development of HAAF. A careful review of the current literature reveals many promising therapeutic approaches to treat or reduce this important limitation to optimal glycemic control.

Opioid Receptor Activation Impairs Hypoglycemic Counterregulation in Humans.

Although intensive glycemic control improves outcomes in type 1 diabetes mellitus (T1DM), iatrogenic hypoglycemia limits its attainment. Recurrent and/or antecedent hypoglycemia causes blunting of protective counterregulatory responses, known as hypoglycemia-associated autonomic failure (HAAF). To determine whether and how opioid receptor activation induces HAAF in humans, 12 healthy subjects without diabetes (7 men, age 32.3 ± 2.2 years, BMI 25.1 ± 1.0 kg/m2) participated in two study protocols in random order over two consecutive days. On day 1, subjects received two 120-min infusions of either saline or morphine (0.1 µg/kg/min), separated by a 120-min break (all euglycemic). On day 2, subjects underwent stepped hypoglycemic clamps (nadir 60 mg/dL) with evaluation of counterregulatory hormonal responses, endogenous glucose production (EGP, using 6,6-D2-glucose), and hypoglycemic symptoms. Morphine induced an ∼30% reduction in plasma epinephrine response together with reduced EGP and hypoglycemia-associated symptoms on day 2. Therefore, we report the first studies in humans demonstrating that pharmacologic opioid receptor activation induces some of the clinical and biochemical features of HAAF, thus elucidating the individual roles of various receptors involved in HAAF's development and suggesting novel pharmacologic approaches for safer intensive glycemic control in T1DM.

Opioid receptor blockade prevents exercise-associated autonomic failure in humans.

Hypoglycemia and exercise both induce the release of ß-endorphin, which plays an important role in the modulation of the autonomic response during subsequent events. Because opioid receptor (OR) blockade during antecedent hypoglycemia has been shown to prevent hypoglycemia-associated autonomic failure, we hypothesized that OR blockade during exercise would prevent exercise-associated autonomic failure (EAAF). We studied 8 healthy subjects on 2 consecutive days, each of whom participated in three different studies in random order. The protocol on day 1 involved one of the following: 1) two 90-min hyperinsulinemic-euglycemic clamps plus naloxone infusion (control); 2) two 90-min hyperinsulinemic-euglycemic clamps with exercise at 60% Vo(2max), plus naloxone infusion (N+); or 3) same protocol as in the N+ group, but with saline infusion only (N-). On day 2, all were studied with stepped hyperinsulinemic-hypoglycemic clamps, using hormone concentrations and glucose turnover as indicators of hypoglycemia counterregulation. Compared with control, N- studies resulted in significantly blunted epinephrine and norepinephrine responses to subsequent hypoglycemia. Conversely, the N+ group exhibited unimpaired hypoglycemia counterregulation, characterized by appropriate increases in epinephrine, norepinephrine, and endogenous glucose production. Thus, OR blockade with naloxone during antecedent exercise prevents the development of acute EAAF by improving the catecholamine responses and by restoring endogenous glucose production.

Magnitude of exercise-induced ß-endorphin response is associated with subsequent development of altered hypoglycemia counterregulation.

CONTEXT: ß-Endorphin release in response to recurrent hypoglycemia is implicated in the pathogenesis of hypoglycemia-associated autonomic failure. OBJECTIVE: We hypothesized that exercise-induced ß-endorphin release will also result in the deterioration of subsequent hypoglycemia counterregulation and that the counterregulatory response will negatively correlate with the degree of antecedent ß-endorphin elevation. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS: Sixteen healthy subjects (six females, aged 26 ± 4.3 yr, body mass index 26.1 ± 5.6 kg/m(2)) were studied with three experimental paradigms on 2 consecutive days. Day 1 consisted of one of the following: 1) two 90-min hyperinsulinemic hypoglycemic clamps (3.3 mmol/liter); 2) two 90-min hyperinsulinemic euglycemic clamps while subjects exercised at 60% maximal oxygen uptake; or 3) two 90-min hyperinsulinemic euglycemic clamps (control). Day 2 followed with hyperinsulinemic (396 ± 7 pmol/liter) stepped hypoglycemic clamps (5.0, 4.4, 3.9, and 3.3 mmol/liter plasma glucose steps). MAIN OUTCOME MEASURES: Day 2 hypoglycemia counterregulatory hormonal response and glucose turnover ([3-(3)H]-glucose) as indicators of recovery from hypoglycemia. RESULTS: There was a significant inverse correlation between plasma ß-endorphin levels during exercise and catecholamine release during subsequent hypoglycemia. Subjects with an exercise-induced rise in ß-endorphin levels to above 25 pg/ml (n = 7) exhibited markedly reduced levels of plasma epinephrine and norepinephrine compared with control (2495 ± 306 vs. 4810 ± 617 pmol/liter and 1.9 ± 0.3 vs. 2.9 ± 0.4 nmol/liter, respectively, P < 0.01 for both). The rate of endogenous glucose production recovery in this group was also much lower than in controls (42 vs. 89%, P < 0.01). CONCLUSIONS: The physiological increase in ß-endorphin levels during exercise is associated with the attenuation of counterregulation during subsequent hypoglycemia.

Opioid receptor blockade improves hypoglycemia-associated autonomic failure in type 1 diabetes mellitus.

CONTEXT: Recurrent hypoglycemia induces hypoglycemia-associated autonomic failure (HAAF), characterized by deterioration in counterregulatory responses. Endogenous opioids may mediate the development of HAAF, and blockade of opioid receptors with naloxone prevented HAAF in nondiabetic subjects. OBJECTIVE: We hypothesized that opioid receptor blockade with naloxone during antecedent hypoglycemia in patients with type 1 diabetes mellitus (T1DM) would prevent the development of HAAF. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS: Eight subjects with T1DM (three women, aged 34 ± 7.4 yr, hemoglobin A1c 7.3 ± 1.1%) were studied on 2 consecutive days on three separate occasions. Day 1 consisted of: 1) two 90-min hypoglycemic clamps (60 mg/dl, N-); 2) two 90-min hypoglycemic clamps (60 mg/dl) with concomitant naloxone infusion (N+); or 3) two 90-min euglycemic clamps (90 mg/dl) with concomitant naloxone infusion (control). Day 2 consisted of hyperinsulinemic stepped hypoglycemic clamps (90, 80, 70, and 60 mg/dl plasma glucose steps). MAIN OUTCOME MEASURES: Day 2 hypoglycemia counterregulatory hormonal response and glucose turnover [(3-(3)H)-glucose] as indicators of recovery from hypoglycemia. RESULTS: Antecedent hypoglycemia in N- group resulted in a markedly decreased epinephrine response and a lower rate of endogenous glucose production (EGP) during subsequent hypoglycemia compared with control (75 ± 17 vs. 187 ± 21 pg/ml, P < 0.05 and 0.8 ± 0.1 vs. 1.4 ± 0.2 mg/kg · min, P < 0.05, respectively). In contrast, in the N+ studies, plasma epinephrine was 164 ± 18 pg/ml and EGP was 1.3 ± 0.2 mg/kg · min during subsequent hypoglycemia, both levels similar to those seen in control studies (P = NS vs. control). Plasma glucagon did not increase with hypoglycemia. CONCLUSIONS: Blockade of endogenous opioids with naloxone during antecedent hypoglycemia improves HAAF in patients with T1DM by ameliorating the epinephrine response and restoring EGP.

Genetic studies reveal the role of the endocrine and metabolic systems in aging.

Aging is a natural process that involves a general decline in many physiological functions, resulting in loss of function and eventually death. Extensive research is being performed in order to elucidate the biology of aging, especially with the advent of newer molecular and genetic methodologies. The endocrine system plays a major role in orchestrating cellular interactions, metabolism, growth, and senescence. Thus, researchers traditionally used hormones as tools to induce and examine specific biological effects that are associated with aging. Furthermore, because our recent knowledge on hormonal action expanded significantly, downstream pathways and genetic determinants currently prevail in aging research. In this review, we will summarize the effects of several hormones on human aging and longevity and present recent data from the Longevity Genes Study performed at Albert Einstein College of Medicine, looking at the phenotype and genotype of centenarians and their offspring. We will demonstrate that genetic factors that are associated with human longevity are heritable and may contribute not only to quantitative longevity but also to protection from age-dependent disease and exceptional good health.

Genetic predisposition to elevated serum thyrotropin is associated with exceptional longevity.

CONTEXT: Exceptional longevity is associated with raised serum TSH. OBJECTIVE: The aim of this study was to examine whether offspring of people with exceptional longevity have elevated serum TSH and whether specific single nucleotide polymorphisms (SNPs) in the TSH-B gene and TSH receptor (TSHR) gene are associated with this phenotype. DESIGN/SETTING/PATIENTS: We measured serum TSH and free T(4) in Ashkenazi Jewish centenarians (n = 232; median age, 97 yr), their offspring (n = 366; median age, 69 yr), and age-matched controls without familial longevity (n = 163; median age, 70 yr). We determined TSH heritability, its distribution, and association with SNPs in the TSH-B and TSHR genes. RESULTS: Offspring had higher median serum TSH [1.68 mIU/liter (97.5% confidence interval, 0.65 to 4.79 mIU/liter)], compared to controls [1.50 mIU/liter (97.5% confidence interval, 0.63 to 3.93 mIU/liter); P = 0.02], with estimated heritability of 0.33 (P = 0.004). Allele frequency of two SNPs in the promoter/enhancer region of TSHR gene, associated with increased serum TSH, was higher in centenarians and their offspring compared to controls (rs10149689 G allele frequency, 0.57 and 0.53 vs. 0.48; P = 0.001 and P = 0.08; odds ratio, 1.56 and 1.22, respectively; and rs12050077 A allele frequency, 0.57 and 0.53 vs. 0.46; P = 0.0001 and P = 0.01; odds ratio, 1.68 and 1.32, respectively). Linkage disequilibrium between the two SNPs was high (r(2) = 0.95), suggesting interaction between them. Furthermore, GA haplotype frequency was significantly higher among centenarians and offspring compared to controls (0.57 and 0.53 vs. 0.46; P = 0.0001 and P = 0.01, respectively). CONCLUSIONS: A heritable phenotype characterized by raised serum TSH is associated with human longevity. Carriers of rs12050077 and rs10149689 SNPs in the TSHR have higher serum TSH, possibly contributing to decreased thyroid function and longevity.

Hypoglycemia-associated autonomic failure is prevented by opioid receptor blockade.

CONTEXT: Repeated hypoglycemia is associated with hypoglycemia-associated autonomic failure (HAAF), a syndrome of defective counterregulation. OBJECTIVE: HAAF increases the risk of severe hypoglycemia in diabetes, although its mechanism remains unresolved. Because beta-endorphin influences the autonomic response to hypoglycemia via opioid receptor activation, we hypothesized that it is also involved in the pathogenesis of HAAF. RESEARCH DESIGN AND METHODS: We asked whether opioid receptor blockade during antecedent hypoglycemia (60 mg/dl) on d 1 would prevent development of HAAF on d 2 in eight nondiabetic subjects (five males, 3 females; age, 28 +/- 3.5 yr; body mass index, 24.2 +/- 2.1 kg/m(2)). On four occasions, d 1 was: 1) two 90-min hypoglycemic clamps (N-); 2) two 90-min hypoglycemic clamps plus naloxone (N+); 3) two euglycemic 90-min clamps (C); or 4) two euglycemic 90-min clamps plus naloxone (C+). RESULTS: Day 1 hypoglycemia caused marked deterioration of d 2 hormonal responses to hypoglycemia, consistent with HAAF-i.e. decreased plasma epinephrine, norepinephrine, and glucagon compared to control (C) (374 +/- 71 vs. 810 +/- 94, 307 +/- 65 vs. 686 +/- 98, and 71 +/- 9 vs. 93 +/- 4 pg/ml, respectively, P < 0.01), as well as in endogenous glucose production (24 vs. 163%; P < 0.01). In contrast, naloxone on d 1 completely prevented the defective counterregulatory responses; epinephrine, norepinephrine, and glucagon (852 +/- 82, 769 +/- 77, and 98 +/- 7 pg/ml) and endogenous glucose production recovery (167%) were identical to those after d 1 euglycemia (P < NS for all). Infusion of naloxone alone during euglycemia on d 1 (C+) had no effect on d 2 responses. CONCLUSIONS: These data suggest that the opioid signaling system is a promising target for further studies to prevent HAAF.

Extreme longevity is associated with increased serum thyrotropin.

CONTEXT: The distribution of serum TSH shifts progressively to higher concentrations with age. OBJECTIVE: The aim of the study was to determine whether the population shift in TSH distribution to higher concentrations with aging extends to people of exceptional longevity, namely centenarians, and to assess the relationship between concentrations of TSH and free T(4) (FT4). DESIGN/SETTING/PATIENTS: We analyzed TSH, FT4, and TSH frequency distribution curves in thyroid disease-free Ashkenazi Jews with exceptional longevity (centenarians; median age, 98 yr), in younger Ashkenazi controls (median age, 72 yr), and in a population of thyroid disease-free individuals (median age, 68 yr) from the U.S. National Health and Nutrition Examination Survey 1998-2002 (NHANES controls). RESULTS: Serum TSH was significantly higher in centenarians [1.97 (0.42-7.15) mIU/liter] than in Ashkenazi controls [1.55 (0.46-4.55) mIU/liter] and NHANES controls [1.61 (0.39-6.29) mIU/liter] (median, 2.5 and 97.5 centiles) (P < 0.001). The TSH frequency distribution curve of centenarians was relatively similar in shape to controls but shifted significantly to higher TSH, including TSH concentration at peak frequency. The TSH distribution curve of the NHANES control group was superimposable to and not significantly different from the Ashkenazi controls. FT4 was similar in centenarians and Ashkenazi controls, and there was a significant inverse correlation between FT4 and TSH in both groups. CONCLUSIONS: The TSH population shifts to higher concentrations with age appear to be a continuum that extends even to people with exceptional longevity. The inverse correlation between TSH and FT4 in our populations suggests that changes in negative feedback may contribute to exceptional longevity.

Role of hepatic glycogen breakdown in defective counterregulation of hypoglycemia in intensively treated type 1 diabetes.

Impairment of hypoglycemic counterregulation in intensively treated type 1 diabetes has been attributed to deficits in counterregulatory hormone secretion. However, because the liver plays a critical part in recovery of plasma glucose, abnormalities in hepatic glycogen metabolism per se could also play an important role. We quantified the contribution of net hepatic glycogenolysis during insulin-induced hypoglycemia in 10 nondiabetic subjects and 7 type 1 diabetic subjects (HbA1c 6.5 +/- 0.2%) using 13C nuclear magnetic resonance spectroscopy, during 2 h of either hyperinsulinemic euglycemia (plasma glucose 92 +/- 4 mg/dl) or hypoglycemia (plasma glucose 58 +/- 3 mg/dl). In nondiabetic subjects, hypoglycemia was associated with a brisk counterregulatory hormone response (plasma epinephrine 246 +/- 38 vs. 2,785 +/- 601 pmol/l during hypoglycemia, plasma norepinephrine 1.9 +/- 0.2 vs. 2.5 +/- 0.3 nmol/l, and glucagon 38 +/- 7 vs. 92 +/- 17 pg/ml, respectively, P < 0.001 in all), and a relative increase in endogenous glucose production (EGP 0.83 +/- 0.14 mg x kg(-1) x min(-1) during euglycemia yet approximately 50% higher with hypoglycemia [1.30 +/- 0.20 mg x kg(-1) x min(-1)], P < 0.001). Net hepatic glycogen content declined progressively during hypoglycemia to 22 +/- 3% below baseline (P < 0.024). By the final 30 min of hypoglycemia, hepatic glycogen fell from 301 +/- 14 to 234 +/- 10 mmol/l (P < 0.001) and accounted for approximately 100% of EGP. In marked contrast, after an overnight fast, hepatic glycogen concentration in type 1 diabetic subjects (215 +/- 23 mmol/l) was significantly lower than in nondiabetic subjects (316 +/- 19 mmol/l, P < 0.001). Furthermore, the counterregulatory response to hypoglycemia was significantly reduced with small increments in plasma epinephrine and norepinephrine (126 +/- 22 vs. 448 +/- 16 pmol/l in hypoglycemia and 0.9 +/- 0.3 vs. 1.6 +/- 0.3 nmol/l, respectively, P < 0.05 for both) and no increase in plasma glucagon. EGP decreased during hypoglycemia with no recovery (1.3 +/- 0.5 vs. 1.2 +/- 0.3 mg x kg(-1) x min(-1) compared with euglycemia, P = NS), and hepatic glycogen concentration did not change significantly with hypoglycemia. We conclude that glycogenolysis accounts for the majority of EGP during the first 90 min of hypoglycemia in nondiabetic subjects. In intensively treated type 1 diabetes, despite some activation of counterregulation, hypoglycemia failed to stimulate hepatic glycogen breakdown or activation of EGP, factors that may contribute to the defective counterregulation seen in such patients.

Fructose normalizes specific counterregulatory responses to hypoglycemia in patients with type 1 diabetes.

We have previously reported that specific counterregulatory responses to hypoglycemia were augmented by an infusion of fructose in nondiabetic humans. We hypothesized that this effect was due to the interaction of a "catalytic" dose of fructose with the regulatory protein for glucokinase in glucose-sensing cells that drive counterregulation. To examine whether fructose could restore counterregulatory responses in type 1 diabetic patients with defective counterregulation, we performed stepped hypoglycemic clamp studies (5.0, 4.4, 3.9, and 3.3 mmol/l glucose steps, 50 min each) in eight intensively treated patients (HbA(1c) 6.4 +/- 0.7%) on two separate occasions: without (control) or with coinfusion of fructose (1.2 mg . kg(-1) . min(-1)). Fructose induced a resetting of the glycemic threshold for secretion of epinephrine to higher plasma glucose concentrations (from 3.3 +/- 0.1 to 3.9 +/- 0.1 mmol/l; P = 0.001) and markedly augmented the increment in epinephrine (by 56%; P < 0.001). The amplification of epinephrine responses was specific; plasma norepinephrine, glucagon, growth hormone, and cortisol were unaffected. Hypoglycemia-induced endogenous glucose production ([3-(3)H]-glucose) rose by 90% (P < 0.001) in the fructose studies, compared with -2.0% (NS) in control. In concert, the glucose infusion rates during the 3.9- and 3.3-mmol/l steps were significantly lower with fructose (2.3 +/- 0.6 and 0.0 +/- 0.0 vs. 5.9 +/- 1.15 and 3.9 +/- 1.0 micromol . kg(-1) . min(-1), respectively; P < 0.001 for both), indicating the more potent counterregulatory response during fructose infusion. We conclude that infusion of fructose nearly normalizes the epinephrine and endogenous glucose production responses to hypoglycemia in type 1 diabetic patients with impaired counterregulation, suggesting that defects in these responses may be dependent on glucokinase-mediated glucose sensing.

Hypoglycemia in diabetes: common, often unrecognized.

Hypoglycemic episodes in patients with diabetes often go unrecognized, and over time, patients may lose the ability to sense hypoglycemia, increasing their risk. Intensive diabetes control is beneficial for patients with diabetes, but it increases their risk of hypoglycemia, underscoring the complexity of diabetes management.

Surgical removal of visceral adipose tissue: effects on insulin action.

Many studies have demonstrated that excess of visceral fat has deleterious effects on insulin action. Mainly, it has been shown to be associated with a decrease in hepatic and peripheral insulin sensitivity, which results in a clinical condition also known as insulin resistance. This report describes a novel experimental method that we employed in order to analyze the particular effects of visceral fat on insulin activity. By extracting visceral fat we were able to distinguish the specific role that it plays in insulin action, and to analyze its effects on the gene expression of a variety of fat-derived peptides, which may be considered to be (at least partially) mediators in the development of the metabolic syndrome and possibly diabetes mellitus.

Plasma HDL levels highly correlate with cognitive function in exceptional longevity.

BACKGROUND: Families of centenarians have high levels of plasma high-density lipoprotein (HDL) cholesterol, which may have neurological as well as cardiovascular protective effects during aging. Because plasma HDL level declines progressively with aging, we examined whether centenarians with higher plasma HDL levels have better cognitive function. METHODS: Total plasma cholesterol, low-density lipoprotein (LDL) cholesterol, HDL, triglycerides, and apolipoprotein levels were measured in a group of centenarians (N = 139; older than 95 years) and were correlated with their cognitive function (measured by Mini-Mental State Examination [MMSE]). RESULTS: Plasma HDL levels correlated significantly with MMSE (r =.32; p <.0001). Each decrease in plasma HDL tertile (74.9 +/- 2.1, 50.6 +/- 0.5, and 36.8 +/- 1.0 mg/dl) was associated with a significant decrease in MMSE (23.4 +/- 1.5, 17.7 +/- 1.8, and 12.4 +/- 1.8; p <.04 for each plasma HDL tertile). As expected, increased plasma apolipoprotein A-I and decreased plasma triglyceride levels were also correlated with a significantly superior cognitive function. Biological markers of hydration and nutritional status did not differ between the groups with the higher or lower plasma HDL or MMSE. CONCLUSIONS: These data demonstrate that cognitive dysfunction in centenarians is associated with a progressive decline in plasma HDL concentrations. This underscores the protective effects of increased plasma HDL and its role in maintaining superior cognition in longevity.